Benzothiazoline compounds which contain a carbonyl group useful for treating cardiovascular disease

ABSTRACT

The invention relates to benzothiazoline derivatives of the formula [I] and salts thereof, which are useful for (i) treating cardiovascular diseases, and (ii) as the active ingredient of pharmaceutical compositions. Formula [I] follows: ##STR1## wherein R 1  is lower alkanoyl; 
     R 2  is one or more group(s) selected from hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen, nitro, halogenolower alkyl and sulfamoyl; 
     R 3  is --COR 8  ; 
     R 8  is hydroxy, lower alkoxy, ##STR2## Z is straight or branched alkylene containing 1 to 6 carbon atoms; m is 0 or 1; n is 0 or 1; and p is 4 or 5.

This is a division of application Ser. No. 503,160 filed Apr. 14, 1983now U.S. Pat. No. 4,479,949.

SUMMARY OF THE INVENTION

This invention relates to benzothiazoline derivatives of the formula [I]and salts thereof, ##STR3## wherein R¹ is lower alkanoyl;

R² is one or more group(s) selected from hydrogen, lower alkyl, loweralkoxy, hydroxy, halogen, nitro, halogeno-lower alkyl and sulfamoyl;

R³ is ##STR4## or --COR⁸ ; R⁴ and R⁵, which may be same or different,each is hydrogen, lower alkyl, cyclohexyl or substituted lower alkylwherein the substituent(s) is/are selected from the group consisting ofhydroxy, phenyl, pyridyl, piperidyl or phenylcarbonyl, and said phenylnucleus may be resubstituted by one or more groups selected from loweralkyl, hydroxy, halogen, lower alkoxy, nitro, cyano, acetamino and loweralkylamino;

R⁶ is hydrogen, alkyl containing 1 to 8 carbon atoms, alkanoylcontaining 2 to 8 carbon atoms, alkenoyl containing 2 to 8 carbon atomsor furylcarbonyl, each of which alkyl, alkanoyl and alkenoyl may besubstituted by one or more groups selected from hydroxy, phenyl andphenylcarbonyloxy, and said phenyl nucleus may be resubstituted by oneor more groups selected from lower alkyl, hydroxy, halogen, loweralkoxy, nitro, cyano, acetamino and lower-alkylamino;

R⁷ is hydrogen, hydroxy, phenyl-lower alkyl or benzoyl;

R⁸ is hydroxy, lower alkoxy, ##STR5## Z is straight or branched alkylenecontaining 1 to 6 carbon atoms; m is 0 or 1;

n is 0 or 1;

p is 4 or 5,

wherein the terms lower alkyl, lower alkoxy and lower alkanoyl refer togroups having 1 to 6 carbon atoms. These compounds include those whereinm is 0 and R² is methoxy or nitro.

BACKGROUND OF THE INVENTION

The compounds of this invention are novel benzothiazoline derivativeswherein the substituent at 3-position on the benzothiazoline ring islower alkanoyl and that at 2-position is phenyl which is resubstitutedby ether group at any position. 2-Phenylbenzothiazoline derivatives werereported by H. Breuer et al. (U.S. Pat. No. 3,720,683), H. D. Cossey etal. (J. Chem. Soc., 1965, 954) and P. J. Palmer et al. (J. Med. Chem.,14, 248). The U.S. Pat. of Breuer et al. relates to2-phenylbenzothiazoline derivatives in which phenyl nucleus issubstituted by alkyl, etc. but not ether group, and the pharmacologicaleffects are for anti-inflammatory and anti-microbial. Cossey et al. andPalmer et al. reported 2-phenylbenzothiazoline derivatives in whichphenyl nucleus is substituted by ether group, but the substituent of3-position is not lower alkanoyl but hydrogen, alkyl, benzyl, etc., andthe pharmacological effect is for anti-microbial.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to benzothiazoline derivatives of the formula[I]. ##STR6##

The compounds of this invention are benzothiazoline derivatives whereinthe substituent at 3-position on the benzothiazoline ring is loweralkanoyl and that at 2-position is phenyl which is resubstituted byether group at any position. The compounds of this invention are notonly new in chemical structure but also found useful for treatment ofcardiovascular diseases and such effect on cardiovascular diseases hasnot been found in the known benzothiazoline derivatives. Cardiovasculardiseases are angina cordis, arrhythmia, thrombosis, etc., and β-blocker,inhibitor of platelet aggregation, calcium antagonist, etc. are used astherapeutic agent. From the pharmacological tests, it is proved that thecompounds of this invention possess a superior platelet anti-aggregationeffect and calcium antagonization, so they are useful for cardiovasculardiseases. Processes for preparing the compounds of this invention aresummarized as follows. The reaction of the compound of the formula [II]with the compound of the formula [III], ##STR7## wherein X is halogen(the same shall be applied hereinafter), or the reaction reversed theabove reaction order, i.e., the reaction of the compound of the formula[IV] with the amine derivative, ##STR8## wherein Y is halogen, carboxyor formyl, and Y and --OH may be jointed to form epoxy ring;

Amine derivative is ##STR9## q is 0 or 1, the same shall be appliedhereinafter.

The processes are explained in detail as follows. The reaction of thehydroxy derivative of the formula [II] with the halide of the formula[III] needs no specific conditions, and known methods which aregenerally used for a reaction or hydroxy derivative with halide can beemployed, but preferably the reaction is carried out in organic solvent(for example, dimethylformamide) in the presence of base (for example,NaH). The reaction of the compound of the formula [IV] with aminederivative is divided into the following (a)-(d) reactions. ##STR10##Specific conditions are unnecessary for the above-mentioned reactions.Methods which are generally used for a reaction of amine derivative withhalide, carboxylic acid derivative, aldehyde derivative or epoxyderivative can be employed.

The compounds of this invention can be converted to acid salts. Saidsalts are obtained by general methods using inorganic acids or organicacids. Examples of pharmaceutically acceptable salts of the compoundsare hydrochloride salt, sulfuric acid salt, phosphoric acid salt, lacticacid salt, maleic acid salt, fumaric acid salt, methanesulfonic acidsalt, p-toluenesulfonic acid salt, oxalic acid salt, etc.

The compounds of the formula [I] have stereoisomers because of theexistence of one or more asymmetric carbon atoms, and these isomers areincluded in this invention.

Examples are shown below, and the compounds of this invention are listedin Table I-IX.

The assignments of the NMR spectra in Table X are made according to thenumbers of the formula [IX]. ##STR11## But, protons (aromatic), not beassigned, are named as aromatic H (Ar--H). Proton of --OCH₃ group isassigned as --OCH₃ (P) when the group is attached to C₂ '-C₆ ' positionof the formula [IX], and assigned as --OCH₃ (A) when the group isattached to the phenyl group which is the substituent of amine moeity ofthe side chain.

EXAMPLE 13-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 86)

1.31 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline and4.21 ml of t-butylamine are dissolved in 10 ml of ethanol and thesolution is refluxed for 1 hour. After cooling, 2 ml of 2N HCl/ethylacetate is added to the reaction mixture and the solution isconcentrated in vacuo. To the residue ether is added to producecrystals. Crystals are collected by filtration to give 1.3 g (81%) ofthe titled compound.

Physical data are shown in Table VII.

The compounds shown in Table VII are prepared by the similar methoddescrived above using corresponding amine derivatives.

EXAMPLE 23-Acetyl-2-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 86)

1.64 g of 3-acetyl-2-[2-(2,3-epoxypropoxy)phenyl]benzothiazoline, 1.82 gof 3-acetyl-2-[2-(3-chloro-2-hydroxypropoxy)phenyl]benzothiazoline and10 ml of t-butylamine are dissolved in 30 ml of ethanol and the solutionis refluxed for 3 hours. The solution is concentrated in vacuo, and theresidue is dissolved in ethyl acetate. The solution is washed withsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate. To this solution 2N HCl/ether is added to produce crystals.Crystals are filtered to give 3.5 g (80%) of the titled compound.

The physical constant of the crystals is the same of the compoundobtained in Example 1.

EXAMPLE 3 3-Acetyl-2-[2-(3-dimethylaminopropoxy)phenyl]benzothiazoline(Compound No. 7)

To the suspension of 0.26 g of the sodium hydride in anhydrous DMF, thesolution of 1.36 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in 5ml of anhydrous DMF is added dropwise under nitrogen atmosphere at roomtemperature. After the addition, the reaction mixture is stirred for 20minutes at room temperature. To the reaction mixture, the solution of0.61 g of 3-dimethylaminopropyl chloride in 10 ml of anhydrous DMF isadded. The reaction mixture is stirred for 2 hours at 80° C., and washedwith n-hexane after cooling and poured into ice-water. The separated oilis extracted with ethyl acetate. The organic layer is washed withN--NaOH solution, water and saturated sodium chloride solution in theorder named and dried over anhydrous magnesium sulfate. Ethy acetate isremoved off in vacuo to give 1.0 g (56%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II and III are prepared by the similarmethod described above using corresponding benzothiazoline derivativesand substituted aminoalkyl halides.

EXAMPLE 4 3-Acetyl-2-[2-(3-aminopropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 1)

By substituting 0.83 g of 3-aminopropyl bromide for 3-dimetylaminopropylchloride in the procedure of Example 3, 1.2 g of the titled compound isobtained.

Physical data are shown in Table I.

EXAMPLE 5 3-Acetyl-2-[2-(3-diethylaminopropoxy)phenyl]benzothiazolinehydrochloride (Compound No. 10)

To the solution of 3.48 g of3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline in 20 ml ofethanol, 10.3 ml of diethylamine is added and the mixture is refluxedfor 2 hours. After removal of ethanol and excess amount of diethylaminein vacuo, ethyl acetate and water are added to the residue. The organiclayer is extracted with N-hydrochloric acid, the acidic layer isalkalinized with N-sodium hydroxide solution and extracted with ethylacetate. The organic layer is washed with saturated sodium chloridesolution and dried over anhydrous magnesium sulfate. The solvent isremoved off in vacuo and the resulting oil is dissolved in methanol. Tothe solution hydrochloric acid in ethyl acetate is added to give 3.4 g(80%) of the titled compound.

Physical data are shown in Table I.

The compounds shown in Table I, II, III and VIII are prepared by thesimilar method described above using corresponding benzothiazolinederivatives and amine derivatives.

EXAMPLE 6 3-Acetyl-2-[2-(3-methylaminopropoxy)phenyl]benzothiazolinefumarate (Copmpound No. 2)

To the solution of 6.55 g of3-acetyl-2-[2-(3-oxopropoxy)phenyl]benzothiazoline in 100 ml ofmethanol, 8.10 g of methylamine hydrochloride and 10.0 g of molecularsieves(3A), smashed into fine pieces, are added. To the suspension 1.26g of sodium cyano borohydride is added and the mixture is stirred for 1hour at room temperature. 2N-Hydrochloric acid is added to the reactionmixture and methanol is removed off in vacuo. The aqueous layer iswashed with ethyl acetate and alkalinized with 2N-sodium hydroxidesolution and extracted wiht ethyl acetate. The organic layer is washedwith saturated sodium chloride solution and dried over anhydrousmagnesium sulfate. The solvent is removed off in vacuo and the resultingoil is dissolved in methanol. To the solution fumaric acid and ethylacetate are added to give 4.9 g (65%) of the titled compound.

Physical data are shown in Table I.

EXAMPLE 73-Acetyl-2-[2-[5-(N-cyclohexyl-N-methlamino)pentyloxy]-5-methoxyphenyl]benzothiazolinefumarate (Compound No. 21)

By substituting 4.50 g of3-acetyl-2-[2-(5-bromopentyloxy)-5-methoxyphenyl]benzothiazoline for3-acetyl-2-[2-(3-chloropropoxy)phenyl]benzothiazoline and 3.40 g ofN-methylcyclohexylamine for diethylamine in the procedure of Example 5,4.2 g (70%) of the titled compound is obtained.

Physical data are shown in Table I.

The compounds shown in Table I are prepared by the similar methoddescribed above using corresponding benzothiazoline derivatives andamine derivatives.

EXAMPLE 83-Acetyl-2-[3-[3-(N-cyclohexyl-N-methylamino)propoxy]-4-hydroxyphenyl]benzothiazolinefumarate (Compound No. 37)

3.64 g of3-acetyl-2-[3-(3-chloropropoxy)-4-hydroxyphenyl]benzothiazoline and 3.40g of N-methylcyclohexylamine are stirred at 100° C. for 1 hour. Aftercooling to room temperature, the reaction mixture is dissolved in 50 mlof chloroform, the solution is washed with N-hydrochloric acid, N-sodiumhydroxide solution and saturated sodium chloride solution in the namedorder and dried over anhydrous magnesium sulfate. Chloroform is removedoff in vacuo and the residue is purified by silica gel columnchromatography. The oily product is dissolved in 20 ml of ethyl acetate.To the solution 0.71 g of fumaric acid in 3 ml of methanol is added togive 2.78 g (50%) of the titled compound.

Physical data are shown in Table II.

The compounds shown in Table II and III are prepared by the similarmethod described above using corresponding bnezothiazoline derivativesand amine derivatives.

EXAMPLE 93-Acetyl-2-[2-[2-[4-(3,4-dimethoxyphenetyl)-1-piperazinyl]ethoxy]phenyl]benzothiazolinedimaleate (Compound No. 57)

3.34 g of 3-acetyl-2-[2-(2-chloroethoxy)phenyl]benzothiazoline and 5.01g of 1-(3,4-dimethoxyphenetyl)piperazine are stirred at 110° C. for 1hour. After cooling to room temperature, the reaction mixture isdissolved in 50 ml of chloroform, the solution is washed withN-hydrochloric acid, N-sodium hydroxide solution and saturated sodiumchloride solution in the named order and dried over anhydrous magnesiumsulfate. Chloroform is removed off in vacuo and the resulting oil isdissolved in 50 ml of ethyl acetate. To the solution 2.32 g of maleicacid in 30 ml of ethyl acetate is added to give 6.24 g (80%) of thetitled compound.

Physical data are shown in Table IV.

The compounds shown in Table I, IV, V, VI and VIII are prepared by thesimilar method described above using corresponding benzothiazolinederivatives and amine derivatives.

EXAMPLE 103-Acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline(Compound No. 97)

To the suspension of 1.59 g of sodium hydride in 30 ml of anhydrous DMF,the solution of 8.13 g of 3-acetyl-2-(2-hydroxyphenyl)benzothiazoline in30 ml of anhydrous DMF is added dropwise under nitrogen atmosphere atroom temperature. After the addition, the reaction mixture is stirredfor 20 minutes at room temperature. To the reaction mixture, thesolution of 4.95 g of ethyl 4-chlorobutyrate in 15 ml of anhydrous DMFis added and stirred for 5 hours at 70° C. After cooling to roomtemperature the reaction mixture is poured into ice-water and extractedwith ethyl acetate.

The organic layer is washed with N-potassium hydroxide solution, water,N-hydrochloric acid and saturated sodium chloride solution in the namedorder and dried over anhydrous magnesium sulfate. The solvent is removedoff and the resulting oil is purified by silica gel columnchromatography to give 8.67 g (75%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 11 3-Acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline(Compound No. 96)

To the solution of 7.71 g of3-acetyl-2-[2-[3-(ethoxycarbonyl)propoxy]phenyl]benzothiazoline in 50 mlof methanol, 2N-sodium hydroxide solution is added and the reactionmixture is stirred for 2 hours at room temperature. Methanol is removedoff in vacuo. The residue is acidified with 2N-hydrochloric acid to give5.72 g (80%) of the titled compound.

Physical data are shown in Table IX.

EXAMPLE 123-Acetyl-2-[2-[3-(morpholinocarbonyl)propoxy]phenyl]benzothiazoline(Compound No. 100)

To the solution of 1.79 g of3-acetyl-2-[2-[3-(carboxy)propoxy]phenyl]benzothiazoline and 0.51 g oftriethylamine in 20 ml of anhydrous methylene chloride, 0.68 g ofisobutyl chloroformate is added dropwise while stirring at -13° C. andstirred additional 10 minutes at the same temperature. To the solution0.44 g of morpholine in 5 ml of methylene chloride is added dropwise.

After the addition, the reaction mixture is stirred for 1 hour underice-water cooling and for 1 hour at room temperature. The reactionmixture is washed with 5% citric acid solution, water, N-potassiumhydroxide solution and saturated sodium chloride solution in the namedoder and dried over anhydrous magnesium sulfate. The solvent is removedoff in vacuo to give 1.60 g (75%) of the titled compound.

Physical data are shown in Table IX.

The compounds shown in Table IX are prepared by the similar methoddescribed above using corresponding amine derivatives.

                                      TABLE I                                     __________________________________________________________________________     ##STR12##                                                                                                      Method                                                                        of                                                                            prepn.   mp (°C.)                    Compd.                            (Examp.                                                                            Yield                                                                             (Recrystn.                         No.  R.sup.2                                                                            R.sup.4 R.sup.5       r No.) (%) solvent)  IR(KBr,                  __________________________________________________________________________                                                         cm.sup.-1)                1*.sup.1                                                                          H    H       H             3 4    65  106-109 (dec.)                                                                          3400, 1660, 1466,                                                             1382, 1232, 748           2*.sup.2                                                                          H    H       CH.sub.3      3 6    65  111-113   3420, 1674, 1458,                                                             1370, 724, 616            3*.sup.1                                                                          H    H       C(CH.sub.3).sub.3                                                                           4 5    75  193-195   3500, 3430, 2950,                                                             2770, 1667, 1585,                                                             1455, 1371, 1320,                                                             1266, 1221, 1095,                                                             741                       4*.sup.1                                                                          H    H                                                                                      ##STR13##    3 5    75  235.5-238.0 (dec.)                                                                      3020, 2940, 1678,                                                             1598, 1488, 1462                                                              1376, 1244, 1226,                                                             1098, 744                 5*.sup.1                                                                          H    H                                                                                      ##STR14##    3 5    70  165-169   3420, 2940, 1676,                                                             1514, 1462, 1378,                                                             1324, 1262, 1250,                                                             1228, 1022, 746           6*.sup.1                                                                          H    CH.sub.3                                                                              CH.sub.3      2 3    80  209-210   3430, 1670, 1460,                                                   (MeOHAcOEt)                                                                             1387, 1354, 1325,                                                             1272, 1245, 1230,                                                             1170, 1103, 1050,                                                             1022, 930, 750           7.sup.                                                                             H    CH.sub.3                                                                              CH.sub.3      3 3    56  92.5-94.5 1678, 1600, 1466,                                                   ((Me.sub.2 CH).sub.2 O                                                                  1376, 1312, 1274,                                                   hexane)   1246, 1218, 1006,                                                             746                       8*.sup.1                                                                          H    CH.sub.3                                                                               ##STR15##    3 5    75  130-142 (MeOHAcOEt)                                                                     3400, 2930, 2910,                                                             1672, 1464, 1380,                                                             1322, 1272, 1242,                                                             1224, 750                 9*.sup.3                                                                          H    CH.sub.3                                                                              CH.sub.2 Ph   3 5    80  159-162   3450, 1676, 1580,                                                             1490, 1466, 1380,                                                             750, 702                 10*.sup.1                                                                          H    CH.sub.2 CH.sub.3                                                                     CH.sub.2 CH.sub.3                                                                           3 5    80  154-156   3480, 3420, 2930,                                                   (MeOHAcOEt)                                                                             1676, 1462, 1378,                                                             1320, 1270, 1240,                                                             1224, 1098, 752          11*.sup.1                                                                          H    CH.sub.2 CH.sub.3                                                                     CH.sub.2 CH.sub.3                                                                           4 5    80  amorph.   3420, 1665, 1465,                                                             1380, 1324, 1270,                                                             1230, 748                12*.sup.1                                                                          H                                                                                   ##STR16##                                                                             ##STR17##    3 5    65  amorph.   2940, 2870, 1684,                                                             1468, 1380, 750          13*.sup.1                                                                          H    CH.sub.2 CH.sub.2 OH                                                                  CH.sub.2 CH.sub.2 OH                                                                        3 9    60  145-149   3320, 1666, 1466,                                                             1380, 1314, 1236,                                                             748                      14*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      3 3    70  221-222   3410, 1665, 1580,                                                   (MeOH)    1465, 1375, 1343,                                                             1270, 1232, 1060,                                                             1030, 753, 740           15*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      4 5    65  199-200   3420, 2930, 1675,                                                             1575, 1460, 1375,                                                             1268, 753, 740           16*.sup.3                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR18##    3 5    70  amorph.   3400, 2930, 1710,                                                             1665, 1575, 1460,                                                             1370, 1268, 1055,                                                             745                      17*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR19##    4 5    60  197-198   3550, 3460, 2950,                                                             1675, 1660, 1482,                                                             1466, 1380, 1272,                                                             1055, 775, 750           18*.sup.3                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                              CH.sub.3      3 3    73  165.5-166 3430, 1672, 1580,                                                   (MeOH)    1492, 1465, 1373,                                                             1207, 1053, 870,                                                              749                      19*.sup.4                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR20##    3 5    80  191.5-192 (dec.) (CH.sub.3                                                    CNMeOH)   3420, 3180, 2860,                                                             1769, 1670, 1498,                                                             1460, 1380, 1368,                                                             1300, 1280, 1209,                                                             1060, 750, 715           20*.sup.4                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR21##    4 5    60  147-148 (CH.sub.3 CN)                                                                   3420, 1670, 1493,                                                             1463, 1372, 1275,                                                             1240, 1208, 1037,                                                             743, 720                 21*.sup.2                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR22##    5 7    70  155.5-157.5                                                                             3420, 2930, 1670,                                                             1466, 1380, 1275,                                                             1207                     22*.sup.4                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR23##    6 7    55  135-137   3440, 1675, 1493,                                                             1465, 1380, 1280,                                                             1210, 1040, 750,                                                              720, 700                 23*.sup.1                                                                          5-OCH.sub.3                                                                        CH.sub.3                                                                               ##STR24##    4 9    80  amorph.   3424, 1664, 1493,                                                             1463, 1377, 1321,                                                             1272, 1262, 1236,                                                             1208, 1155, 1028                                                              748                      24*.sup.1                                                                          5-OCH.sub.3                                                                         ##STR25##                                                                            CH.sub.2 CH.sub.2 OH                                                                        4 9    70  amorph.   3336, 1664, 1493,                                                             1464, 1397, 1274,                                                             1208, 1036, 748          25*.sup.1                                                                          5-OCH.sub.3                                                                         ##STR26##                                                                             ##STR27##    4 9    75  amorph.   3424, 1668, 1510,                                                             1496, 1466, 1272,                                                             1262, 1237, 1208,                                                             1025, 750                26*.sup.1                                                                          5-Cl CH.sub.3                                                                              CH.sub. 3     3 3    70  193-195.5 3420, 1678, 1466,                                                   ((Me.sub.2 CH).sub.2 O                                                                  1376, 1226 1110,                                                    Et.sub.2 O)                                                                             1035, 764                27*.sup.1                                                                          3-NO.sub.2                                                                         CH.sub.3                                                                               ##STR28##    3 5    70  103-106   3420, 1668, 1598,                                                             1528, 1464, 1376,                                                             1348, 1319, 1270,                                                             1225, 742                28*.sup.2                                                                          5-NO.sub.2                                                                         CH.sub.3                                                                              CH.sub.3      3 3    65  159-160 (dec.)                                                                          3420, 1670, 1610,                                                   (MeOHCH.sub.3 CN)                                                                       1591, 1515, 1463,                                                             1379, 1340, 1268,                                                             1225, 1078, 1032,                                                             980, 745                 29*.sup.2                                                                          5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR29##    3 5    55  168-169 (dec.) (MeOHCH.sub.3                                                  CN)       3460, 1693, 1670,                                                             1588, 1512, 1461,                                                             1375, 1336, 1265,                                                             1212 1074, 741           30*.sup.2                                                                          5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR30##    4 5    60  176.5-178 (dec.) (MeOHCH.sub.3                                                CN)       3420, 1695, 1591,                                                             1510, 1465, 1379,                                                             1341, 1267, 1226,                                                             1079, 755                31*.sup.2                                                                          5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR31##    5 7    70  172-174 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1710, 1675,                                                             1591, 1511, 1467,                                                             1380, 1336, 1265,                                                             1230, 1078, 982,                                                              747                      32*.sup.2                                                                          5-NO.sub.2                                                                         CH.sub.3                                                                               ##STR32##    6 7    70  178-180 (dec.) (MeOHCH.sub.3                                                  CN)       3430, 1715, 1679,                                                             1591, 1511, 1461,                                                             1377, 1335, 1268,                                                             1227, 1077, 982,                                                              749                      33*.sup.5                                                                          5-NO.sub.2                                                                         H                                                                                      ##STR33##    3 9    55  83-85 (AcOEt)                                                                           3400, 3290, 1678,                                                             1612, 1592, 1580,                                                             1522, 1466, 1348,                                                             1338, 1268, 1080,                                                             748                      34*.sup.2                                                                          3-OCH.sub.3 5-NO.sub.2                                                             CH.sub.3                                                                               ##STR34##    3 5    65  157-159 (MeOH CH.sub.3                                                                  3420, 1705, 1677,                                                             1570, 1530, 1463,                                                             1370, 1340, 1294,                                                             1273 1213, 1194,                                                              1162, 1062, 981,                                                              763,                     __________________________________________________________________________                                                         738                       *.sup.1 Hydrochloride                                                         *.sup.2 Fumarate                                                              *.sup.3 Maleate                                                               *.sup.4 Oxalate                                                               *.sup.5 Monohydrate                                                      

                                      TABLE II                                    __________________________________________________________________________     ##STR35##                                                                                           Method                                                                        of         mp(°C.)                              Compd.                 prepn. Yield                                                                             (Recrystn.                                  No.  R.sup.2                                                                            R.sup.4                                                                           R.sup.5                                                                              r (Examp. No.)                                                                         (%) solvent)                                                                              IR(KBr, cm.sup.-1)                  __________________________________________________________________________    35*.sup.1                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                             3 3      70  162-164 3420, 1716, 1680, 1606, 1586,                                                 1463, 1381, 1306, 1288, 954         36   4-OH CH.sub.3                                                                          CH.sub.3                                                                             3 8      30  oil     3340, 1675, 1585, 1510, 1480                                                  1430, 1300, 1270, 1141, 750                                                   (neat)                              37*.sup.1                                                                          4-OH CH.sub.3                                                                           ##STR36##                                                                           3 8      50  130-133 (dec.)                                                                        3400, 1670, 1575, 1510, 1462,                                                 1430, 1375, 1340, 1320, 1272,                                                 1230, 1208, 985, 745                38*.sup.2                                                                          4-OCH.sub.3                                                                        CH.sub.3                                                                           ##STR37##                                                                           4 5      85  amorph. 3400, 1660, 1512, 1460, 1380,                                                 1340, 1255, 1135, 1020, 750         39*.sup.2                                                                          4-NO.sub.2                                                                         CH.sub.3                                                                           ##STR38##                                                                           3 5      70  115-117 3420, 1662, 1606, 1513, 1464,                                                 1375, 1343, 1314, 1272, 745         40*.sup.2                                                                          6-NO.sub.2                                                                         CH.sub.3                                                                           ##STR39##                                                                           3 5      65   69-73  3430, 1665, 1610, 1580, 1510,                                                 1468, 1378, 1318, 1290, 1226,                                                 748                                 __________________________________________________________________________     *.sup.1 Fumarate                                                              *.sup.2 Hydrochloride                                                    

                                      TABLE III                                   __________________________________________________________________________     ##STR40##                                                                                             Method                                                                        of         mp(°C.)                            Compd.                   prepn. Yield                                                                             (Recrystn.                                No.  R.sup.2                                                                            R.sup.4                                                                             R.sup.5                                                                              r (Examp. No.)                                                                         (%) solvent)                                                                            IR(KBr, cm.sup.-1)                  __________________________________________________________________________    41*.sup.1                                                                          H    CH.sub.3                                                                            CH.sub.3                                                                             2 3      80  amorph.                                                                             3410, 1664, 1510, 1464, 1378,                                                 1234, 748                           42*.sup.1                                                                          H    CH.sub.3                                                                            CH.sub.3                                                                             3 3      75  oil   3400, 1660, 1610, 1580, 1460,                                                 1380, 1230, 1174, 750                                                         (neat)                              43*.sup.1                                                                          H    CH.sub.3                                                                            CH.sub.3                                                                             4 5      80  amorph.                                                                             3420, 2940, 1666, 1510, 1464,                                                 1376, 1244, 1174, 748               44*.sup.1                                                                          H    CH.sub.3                                                                             ##STR41##                                                                           3 5      75  amorph.                                                                             3420, 2930, 1684, 1510, 1462,                                                 1376, 1326, 1268, 1244, 1230,                                                 1174, 748                           45*.sup.1                                                                          H    CH.sub.3                                                                             ##STR42##                                                                           4 5      75  amorph.                                                                             3420, 2940, 1666, 1510, 1464,                                                 1376, 1328, 1270, 1244, 1174,                                                 748                                 46*.sup.1                                                                          H    CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                    3 5      75  amorph.                                                                             3420, 2930, 1662, 1506, 1460,                                                 1374, 1324, 1266, 1238, 1172,                                                 748                                 47   3-OH CH.sub.3                                                                             ##STR43##                                                                           3 8      40  oil   3330, 1666, 1575, 1502, 1461,                                                 1376, 1340, 1270, 1216, 1121,                                                 1025, 745 (neat)                    48*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             3 3      80  amorph.                                                                             3420, 1662, 1510, 1460, 1375,                                                 1335, 1256, 1230, 1132, 1025,                                                 746                                 49*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             4 5      70  amorph.                                                                             3420, 1665, 1510, 1462, 1375,                                                 1255, 1230, 1132, 1025, 750         50*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                             ##STR44##                                                                           3 5      75  amorph.                                                                             3420, 1666, 1512, 1465, 1378,                                                 1255, 1230, 1135, 1027, 750         51*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                             ##STR45##                                                                           4 5      70  amorph.                                                                             3400, 1663, 1510, 1460, 1378,                                                 1255, 1132, 1025, 746               52*.sup.1                                                                          3-NO.sub.2                                                                         CH.sub.3                                                                             ##STR46##                                                                           3 5      75  amorph.                                                                             3420, 1665, 1618, 1530, 1463,                                                 1376, 1350, 1320, 1270, 1081,                                                 1027, 749                           53*.sup.1                                                                          3-OCH.sub.3                                                                        CH.sub.3                                                                            CH.sub.3                                                                             3 5      65  amorph.                                                                             3410, 2940, 1656, 1582, 1452,            5-OCH.sub.3                          1412, 1368, 1318, 1220, 1112,                                                 740                                 54*.sup.1                                                                          3-OCH.sub.3 5-OCH.sub.3                                                            CH.sub.3                                                                             ##STR47##                                                                           3 5      60  amorph.                                                                              3440, 2950, 1664, 1588, 1462,                                                1420, 1380, 1338, 1236, 1124,                                                 752                                 55*.sup.1                                                                          3-OCH.sub.3 5-OCH.sub.3                                                            CH.sub.3                                                                             ##STR48##                                                                           4 5      75  amorph.                                                                             3420, 2932, 1664, 1589, 1458,                                                 1419, 1379, 1327, 1271, 1229,                                                 1122                                __________________________________________________________________________     *.sup.1 Hydrochloride                                                    

                                      TABLE IV                                    __________________________________________________________________________     ##STR49##                                                                                                Method                                            Compd.                      of prepn.                                                                            Yield                                                                             mp (°C.)                        No.  R.sup.2                                                                            R.sup.6         r (Examp. No.)                                                                         (%) (Recrystn. solvent)                                                                     IR(KBr,                      __________________________________________________________________________                                                     cm.sup.-1)                   56*.sup.1                                                                          H    CH.sub.3        3 3      65  213-215   3400, 1664, 1460, 1376,                                                       1322,                                                                         1272, 1226, 746              57*.sup.2                                                                          H                                                                                   ##STR50##      2 9      80  181-182 (dec.) (MeOHCH.sub.3                                                            3430, 1683, 1615, 1573,                                                       1513, 1460, 1375, 1352,                                                       1319, 1259, 1222, 1095,                                                       1022, 860, 755               58*.sup.2                                                                          H                                                                                   ##STR51##      3 9      70  172-173 (dec.) (MeOHCH.sub.3                                                            3430, 1687, 1619, 1570,                                                       1515, 1460, 1378, 1352,                                                       1321, 1260, 1238, 1225,                                                       1098, 1024, 864 755,                                                          743                          59*.sup.3                                                                          H                                                                                   ##STR52##      2 9      60  144-146 (dec.) (MeOHCH.sub.3                                                            3430, 1705, 1682, 1651,                                                       1586, 1511, 1459, 1374,                                                       1263, 1223, 1152, 1022,                                                       751                          60*.sup.3                                                                          H                                                                                   ##STR53##      3 9      75  149-151 (dec.) (CH.sub.3 CN)                                                            3420, 1712, 1679, 1647,                                                       1590, 1513, 1460, 1375,                                                       1262, 1227, 11155 1023,                                                       975, 750                     61*.sup.4                                                                          H                                                                                   ##STR54##      3 9      85  131-132 (dec.) (MeOHEt.sub.2                                                            3420, 1670, 1640, 1585,                                                       1512, 1459, 1374, 1260,                                                       1138, 1022, 740              62*.sup.2                                                                          5-OCH.sub.3                                                                         ##STR55##      3 9      60  181-182 (dec.) (MeOHCH.sub.3                                                            3430, 1671, 1618, 1572,                                                       1492, 1462, 1377, 1353,                                                       1322, 1260, 1236, 1207,                                                       1155, 1099, 1025, 862,                                                        745                          63*.sup.5                                                                          5-OCH.sub.3                                                                         ##STR56##      4 9      65  197.5-198.5 (MeOHCH.sub.3 CN)                                                           3420, 1708, 1668, 1575,                                                       1495, 1461, 1373, 1295,                                                       1267, 1233, 1205, 1152,                                                       1022, 973, 743               64*.sup.2                                                                          5-OCH.sub.3                                                                         ##STR57##      5 9      70  195.5-197.5 (dec.)                                                                      3440, 1664, 1580, 1500,                                                       1466, 1381, 1208, 1023,                                                       865                          65*.sup.2                                                                          5-OCH.sub.3                                                                         ##STR58##      6 9      60  188-189 (MeOHCH.sub.3 CN)                                                               3430, 1670, 1618, 1570,                                                       1465, 1380, 1354, 1260,                                                       1240, 1210, 1027, 865        66*.sup.2                                                                          5-OCH.sub.3                                                                        CH.sub.2 CH.sub.2 OH                                                                          4 9      80  186-187 (dec.)                                                                          3480, 1700, 1672, 1620,                                                       1575,                                                               (MeOHCH.sub.3 CN)                                                                       1490, 1468, 1380, 1359,                                                       1276,                                                                         1210, 1070, 865, 746         67*.sup.1                                                                          5-OCH.sub.3                                                                         ##STR59##      4 9      60  239-240 (dec.)                                                                          3420, 1674, 1588, 1500,                                                       1460, 1420, 1376, 1232,                                                       1212, 1120, 1040, 758        68*.sup.2                                                                          5-OCH.sub.3                                                                         ##STR60##      4 9      80  175-177 (EtOHCH.sub.3 CN)                                                               3430, 1664, 1571, 1492,                                                       1465, 1379, 1360, 1277,                                                       1208, 1102, 1062, 864        69*.sup.5                                                                          5-OCH.sub.3                                                                         ##STR61##      4 9      70  170-173   3440, 1491, 1465, 1379,                                                       1274, 1209, 752              70*.sup.2                                                                          5-OCH.sub.3                                                                         ##STR62##      4 9      75  181-182.5 (dec.) (MeOHCH.sub.3                                                          3450, 1710, 1672, 1580,                                                       1466, 1378, 1355, 1330,                                                       1210, 1123, 862, 746         71*.sup.3                                                                          5-OCH.sub.3                                                                         ##STR63##      3 9      65  130-131 (dec.) (AcOEt)                                                                  3420, 1701, 1660, 1641,                                                       1590, 1515, 1499, 1463,                                                       1372, 1272, 1260, 1231,                                                       1207, 1140, 1023, 980,                                                        750                          72*.sup.6                                                                          5-OCH.sub.3                                                                         ##STR64##      3 9      70  175-176 (dec.) (CH.sub.3 CN)                                                            3430, 1641, 1580, 1509,                                                       1462, 1373, 1260, 1207,                                                       1136, 1022, 975, 863,                                                         745                          73*.sup.2                                                                          5-NO.sub.2                                                                         (CH.sub.2).sub.7 CH.sub.3                                                                     3 9      75  176.5-177.5                                                                             3420, 1676, 1610, 1580,                                                       1510,                                                               (MeOHCH.sub.3 CN)                                                                       1468, 1380, 1342, 1272,                                                       1080,                                                                         865, 748                     74*.sup.2                                                                          5-NO.sub.2                                                                          ##STR65##      3 9      90  156.5-158 (dec.) (MeOHCH.sub.3                                                          3420, 1660, 1573, 1508,                                                       1461, 1378, 1338, 1262,                                                       1231, 1189, 1138, 1075,                                                       1020, 860, 741, 710          75*.sup.7                                                                          5-NO.sub.2                                                                         CO(CH.sub.2).sub.6 CH.sub.3                                                                   3 9      70  90-92.5   3450, 1650, 1590, 1466,                                                       1340                                                                (CHCl.sub.3Et.sub.2 O)                                                                  1270, 748, 712               76*.sup.2                                                                          5-NO.sub.2                                                                          ##STR66##      3 9      75  144-145 (dec.)                                                                          3410, 1661, 1572, 1508,                                                       1462, 1378, 1337, 1267,                                                       1225, 1074, 1011, 860,                                                        741                          77*.sup.2                                                                          5-NO.sub.2                                                                          ##STR67##      3 9      70  153-155 (dec.) (EtOH)                                                                   392, 1654, 1576, 1508,                                                        1465, 1381, 1340, 1270,                                                       1192, 1077, 1013, 863,                                                        745, 701                     78*.sup.8                                                                          5-NO.sub.2                                                                          ##STR68##      3 9      75  199-202 (dec.) (DMSOH.sub.2                                                             3400, 1663, 1647, 1597,                                                       1510, 1463, 1398, 1380,                                                       1339, 1271, 1225, 1168,                                                       718                          79*.sup.4                                                                          5-NO.sub.2                                                                          ##STR69##      3 9      80  181-183 (dec.) (MeOHCH.sub.3                                                            3492, 3400, 1671, 1618,                                                       1593, 1513, 1484, 1466,                                                       1384, 1339, 1273, 1229,                                                       1080, 759, 742               80*.sup.1                                                                          3-OCH.sub.3 5-NO.sub.2                                                              ##STR70##      3 9      75  147-150 (dec.) (MeOHH.sub.2                                                             3410, 1662, 1514, 1460,                                                       1374, 1338, 1291, 1236,                                                       1139, 1098, 1060, 1021,                                                       951, 747                     __________________________________________________________________________     *.sup.1 Dihydrochloride-                                                      *.sup.2 Dimaleate-                                                            *.sup.3 Fumarate-                                                             *.sup.4 Hydrochloride-                                                        *.sup.5 Difumarate-                                                           *.sup.6 Maleate-                                                              *.sup.7 Oxalate-                                                               *.sup.8 Dioxalate-                                                      

                                      TABLE V                                     __________________________________________________________________________     ##STR71##                                                                                               Method                                             Compd.                     of prepn.                                                                            Yield                                                                             mp (°C.)                         No.  R.sup.2                                                                            R.sup.6        r (Examp. No.)                                                                         (%) (Recrystn. solvent)                                                                     IR(KBr,                       __________________________________________________________________________                                                    cm.sup.-1)                    81*  4-OCH.sub.3                                                                         ##STR72##     4 9      85  168-169 (MeOHCH.sub.3 CN)                                                               3450, 1682, 1620, 1580,                                                       1515, 1460, 1375, 1359,                                                       1336, 1260, 1240, 1139,                                                       1027, 865,                    __________________________________________________________________________                                                    745                            *Dimalate-                                                               

                                      TABLE VI                                    __________________________________________________________________________     ##STR73##                                                                                                 Method                                                                        of prepn. mp(°C.)                         Compd.                       (Examp.                                                                             Yield                                                                             (Recrystn.                             No.   R.sup.2                                                                            R.sup.6         r No.)  (%) solvent)  IR(KBr,                      __________________________________________________________________________                                                     cm.sup.-1)                   82*.sup.1                                                                           H                                                                                   ##STR74##      3 9     60  175-177 (dec.) (MeOHCH.sub.3                                                            3420, 1712, 1660, 1575,                                                       1509, 1462, 1373, 1300,                                                       1260, 1233, 1171, 1024,                                                       970,  757                    83*.sup.2                                                                           3-OCH.sub.3                                                                         ##STR75##      3 9     85  164-165 (MeOHCH.sub.3 CN)                                                               3430, 1665, 1619, 1570,                                                       1510, 1460, 1375, 1353,                                                       1325, 1256, 1235, 1132,                                                       1025,  865                   84*.sup.2                                                                           3-OCH.sub.3                                                                         ##STR76##      4 9     80  167-168 (MeOHCH.sub.3 CN)                                                               3430, 1670, 1570, 1450,                                                       1370, 1355, 1325, 1255,                                                       1240, 1130, 1025,  865,                                                       750                          85*.sup.2                                                                           3-OCH.sub.3 5-OCH.sub.3                                                             ##STR77##      4 9     70  163.5-165.5                                                                             3450, 1670, 1577, 1499,                                                       1460, 1379, 1328, 1261,                                                       1236, 1122, 1024,            __________________________________________________________________________                                                     866                           *.sup.1 Difumarate                                                            *.sup.2 Dimaleate                                                        

                                      TABLE VII                                   __________________________________________________________________________     ##STR78##                                                                                     Method                                                                        of         mp(°C.)                                    Compd.           prepn. Yield                                                                             (Recrystn.                                        No.  R.sup.4                                                                             R.sup.5                                                                             (Examp. No.)                                                                         (%) solvent)                                                                              IR(KBr, cm.sup.-1)                        __________________________________________________________________________    86*  H     C(CH.sub.3).sub.3                                                                   1      81  188-192 3350, 2980, 2790, 1672, 1660,                              2          (CHCl.sub.3Et.sub.2 O)                                                                1470, 1384, 1224,  750                    87a* CH.sub.3                                                                             ##STR79##                                                                          1      35  208-210 3225, 2940, 1686, 1464, 1382,  744        87b* CH.sub.3                                                                             ##STR80##                                                                          1      30  143-146 3350, 2940, 1672, 1464, 1382,  748        88*  CH.sub.2 CH.sub.3                                                                   CH.sub.2 CH.sub.3                                                                   1      75  amorph. 3400, 2930, 1658, 1600, 1460,                                                 1380, 1326, 1274, 1234, 1102,                                                 1028,  750                                __________________________________________________________________________     *Hydrochloride                                                                Compound 87a is the diastereoisomer of compound 87b.                     

                                      TABLE VIII                                  __________________________________________________________________________     ##STR81##                                                                                                 Method                                                                        of prepn. mp(°C.)                         Compd.                       (Examp.                                                                             Yield                                                                             (Recrystn.                             No.   R.sup.2                                                                            R.sup.9         r No.)  (%) solvent)  IR(KBr,                      __________________________________________________________________________                                                     cm.sup.-1)                   89*.sup.1                                                                           H                                                                                   ##STR82##      3 5     70  124-127   3430, 2940, 1674, 1466,                                                       1380,  746                   90    H                                                                                   ##STR83##      3 3     55  121-122.5 1676, 1466, 1456, 1374,                                                       1324, 1276, 1252, 1230,                                                       1116,  752                   91*.sup.2                                                                           H                                                                                   ##STR84##      3 9     75  184-186 (dec.)                                                                          3450, 1728, 1685, 1605,                                                       1465, 1384, 1280, 1254,                                                       1239,  758                   92*.sup.2                                                                           5-OCH.sub.3                                                                         ##STR85##      4 9     70  148-150 (iso-PrOH AcOEtEt.sub.2                                                         3420, 1705, 1669, 1493,                                                       1463, 1379, 1320, 1275,                                                       1237, 1207, 1140,  745       93*.sup.3                                                                           5-OCH.sub.3                                                                         ##STR86##      4 9     80  182-184 (MeOHCH.sub.3 CN)                                                               3450, 1720, 1671, 1595,                                                       1461, 1378, 1278, 1208,                                                       702                          94*.sup.3                                                                           5-NO.sub.2                                                                          ##STR87##      3 9     75  175-178 (dec.) (MeOHCH.sub.3                                                            3408, 1664, 1610, 1592,                                                       1509, 1459, 1381, 1340,                                                       1270, 1226, 1074,  744,                                                       700                          95*.sup.3                                                                           5-NO.sub.2                                                                          ##STR88##      3 9     70  190-191 (dec.) (MeOHCH.sub.3                                                            3424, 1718, 1689, 1608,                                                       1594, 1510, 1465, 1376,                                                       1339, 1269, 1195,  744,                                                       701                          __________________________________________________________________________     *.sup.1 Hydrochloride                                                         *.sup.2 Fumarate                                                              *.sup.3 Oxalate                                                          

                                      TABLE IX                                    __________________________________________________________________________     ##STR89##                                                                                             Method                                                                        of prepn. mp(°C.)                             Compd.                   (Examp.                                                                             Yield                                                                             (Recrystn.                                 No.  R.sup.8           r No.)  (%) solvent) IR(KBr, cm.sup.-1)                __________________________________________________________________________    96   OH                3 11    80  121-122.5                                                                              3420, 1725, 1636, 1465,                                                       1387,                                                                (AcOEtEt.sub.2 O                                                                       1272, 1242, 1231, 1176,                                                       1100,                                                                Me.sub.2 CHOCHMe.sub.2)                                                                1040,  745                        97   OCH.sub.2 CH.sub.3                                                                              3 10    75  oil      1735, 1679, 1601, 1491,                                                       1468,                                                                         1380, 1325, 1273, 1247,                                                       1230,                                                                         1178, 1100, 1028,  730                                                        (neat)                            98                                                                                  ##STR90##        3 12    65  amorph.  3310, 1650, 1510, 1461, 1375,                                                 321, 1257, 1230, 1023,  745        99*                                                                                ##STR91##        3 12    80  195.5-197 (dec.) (EtOHH.sub.2 O)                                                       3430, 1652, 1465, 1376, 1328,                                                 243, 1159, 1022,  975,  747,                                                  42                                100                                                                                 ##STR92##        3 12    75  133-134 (AcOEt)                                                                        1670, 1639, 1599, 1460, 1373,                                                 325, 1267, 1227, 1100, 1098,                                                  1028,  750                        __________________________________________________________________________     *Fumarate                                                                

      X NMR No.  δ (ppm), J =      Hz      1 DMSO-d.sub.6     ##STR93##        OC.sub.--H.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.70-8.20     (1H, m, C.sub.4H), 8.00-8.80 (3H, br, N.sub.--H.sub.2 and .sub.--HCl)     2 DMSO-d.sub.6      ##STR94##      ##STR95##        (1H, m, C.sub.4H), 9.13 (3H, br s, N.sub.--H and CO.sub.2.sub.--H     × 2)      3 DMSO-d.sub.6     ##STR96##      ##STR97##        9.40 (2H, br, N.sub.--H and .sub.--HCl)      4 DMSO-d.sub.6     ##STR98##      ##STR99##        (1H, m, C.sub.4H), 9.50-10.53 (2H, br, N.sub.--H and .sub.--HCl)   5     DMSO-d.sub.6      ##STR100##        OC.sub.--H.sub.3), 3.74 (3H, s, OC.sub.--H.sub.3), 4.23 (2H, t, J =     6.0, OC.sub.--H.sub.2), 6.60-7.50 (11H, m, C.sub.2H and ArH), 7.70-8.10      (1H, m, C.sub.4H), 9.50 (2H, br s, N.sub.--H and .sub.--HCl)   6     DMSO-d.sub.6      ##STR101##        6.73-7.63 (8H, m, C.sub.2H and ArH), 7.80-8.23 (1H, m, C.sub.4H),     11.53 (1H, br s, .sub.--HCl)      7 CDCl.sub.3     ##STR102##        OC.sub.--H.sub.2 CH.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH),     7.70-8.30 (1H, m, C.sub.4H)      8 DMSO-d.sub.6     ##STR103##      ##STR104##        (1H, m, C.sub.4H), 10.80-11.50 (1H, br, .sub.--HCl)   9 DMSO-d.sub.6      ##STR105##      ##STR106##      ##STR107##        CO.sub.2.sub.--H × 2)      10 DMSO-d.sub.6     ##STR108##        6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2), 4.22 (2H,     t, J = 5.5, OC.sub.--H.sub.2), 6.70-7.40 (8H, m, C.sub.2H and ArH),     7.70-8.10   (1H, m, C.sub.4H), 10.90-11.50 (1H, br, .sub.--HCl)  11     DMSO-d.sub.6      ##STR109##        3.40 (6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2),     3.90-4.33 (2H, m, OC.sub.--H.sub.2), 6.60-7.57 (8H, m, C.sub.2H and     ArH), 7.67-8.23   (1H, m, C.sub.4H), 10.63-11,40 (1H, br, .sub.--HCl)     12 DMSO-d.sub.6      ##STR110##        3.90-4.50 (2H, m, OC.sub.--H.sub.2), 6.70-7.50 (8H, m, C.sub.2H and   H     Ar), 7.70-8.10 (1H, m, C.sub.4H), 10.10-10.60   (1H, br, .sub.--HCl)  13     DMSO-d.sub.6      ##STR111##        (4H, m, C.sub.--H.sub.2 OH × 2), 4.17 (2H, t, J =               H      5.5, OC.sub.--.sub.2), 4.50-5.20 (2H, br, O.sub.--H × 2),     6.60-7.50 (8H, m,   C.sub.2H and ArH), 7.70-8.20 (1H, m, C.sub.4H),     10.00-10.60 (1H, br, .sub.--HCl)      14 DMSO-d.sub.6     ##STR112##      ##STR113##        7.40 (6H, m, C.sub.2H and ArH), 7.73-8.16 (1H, m, C.sub.4H), 10.50-11.     73 (1H, br, .sub.--HCl)      15 CDCl.sub.3     ##STR114##      ##STR115##        6.70-7.30 (6H, m, C.sub.2H and ArH), 7.56-8.30 (1H, m, C.sub.4H),     11.87-12.80 (1H, br, .sub.--HCl)      16 DMSO-d.sub.6     ##STR116##      ##STR117##        6.52 (1H, dd, J = 6.0, 3.5, C.sub.4 'H), 6.63-7.27 (6H, m, C.sub.2H     and ArH), 7.63-8.17 (1H, m, C.sub.4H), 10.00-   14.50 (2H, br, CO.sub.2.s     ub.--H × 2)      17 CDCl.sub.3     ##STR118##      ##STR119##        C.sub.4 'H), 6.57-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.23 (1H, m,     C.sub.4 H), 11.40-12.23 (1H, br, .sub.-HCl)      18 CDCl.sub.3     ##STR120##      ##STR121##        C.sub.6 'H), 6.63-7.30 (6H, m, C.sub.2H and ArH), 7.57-8.30 (1H, m,     C.sub.4H), 12.65-15.50 (2H, br, CO.sub.2.sub.--H × 2)      19 DMSO-d.sub.6      ##STR122##      ##STR123##        C.sub.6 'H), 6.62-7.37 (6H, m, C.sub.2H and ArH), 7.63-8.20 (1H, m,     C.sub.4H), 9.82 (2H, br s, CO.sub.2.sub.--H × 2)  20 DMSO-d.sub.6      ##STR124##      ##STR125##        6.62-7.40 (6H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m, C.sub.4H),     9.75 (2H, br s, CO.sub.2.sub.--H × 2)      21 DMSO-d.sub.6     ##STR126##      ##STR127##      ##STR128##      22 DMSO-d.sub.6     ##STR129##      ##STR130##        6.63-7.40 (6H, m, C.sub.2H and ArH), 7.67-8.20 (1H, m, C.sub.4H),     9.17 (2H, br s, CO.sub.2.sub.-- H × 2)      23 DMSO-d.sub.6     ##STR131##      ##STR132##        3.80-4.20 (2H, m, OC.sub.--H.sub.2), 6.45 (1H, d, J = 2.0, C.sub.6     'H), 6.60-7.30 (9H, C.sub.2H and ArH), 7.70-8.10   (1H, m, C.sub.4H),     10.90-11.50 (1H, br, .sub.--HCl)      24 DMSO-d.sub.6     ##STR133##        3.23 (3H, s, OC.sub.--H.sub.3 (P)), 3.70-4.00 (2H, m, C.sub.--H.sub.2     OH), 3.90-4.30 (2H, m, OC.sub.--H.sub.2), 4.67 (1H, s, O.sub.--H),     6.41 (1H, d, J = 2.0, C.sub.6 'H), 6.70-7.30 (6H, m, C.sub.2H and ArH),     7.70-8.20 (1H, m, C.sub.4H), 9.90-10.40   (1H, br, .sub.--HCl)  25     DMSO-d.sub.6      ##STR134##        3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.65 (3H, s, OC.sub.--H.sub.3     (A)), 3.71 (3H, s, OC.sub.--H.sub.3      (A)), 3.90-4.30 (2H, m, OC.sub.--H.sub.2),   6.42 (1H, d, J = 2.0,     C.sub.6 'H), 6.60-7.20 (9H, m, C.sub.2H and ArH), 7.70-8.20 (1H, m,     C.sub.4H), 10.90-11.30   (1H, br, .sub.--HCl)      26 DMSO-d.sub.6     ##STR135##      ##STR136##        m, C.sub.4H), 11.00-11.90 (1H, br, .sub.--HCl)  27 CDCl.sub.3      ##STR137##      ##STR138##        m, C.sub.4H), 7.77 (1H, dd, J = 8.0, 2.0, C.sub.4 'H), 11.30-12.20     (1H, br, .sub.--HCl)      28 DMSO-d.sub.6     ##STR139##      ##STR140##        C.sub.7H), 7.28 (1H, d, J = 9.0, C.sub.3 'H), 7.72 (1H, d, J = 3.0,     C.sub.6 'H), 7.83-8.10 (1H, m, C.sub.4H), 8.15 (1H,   dd, J = 9.0, 3.0,     C.sub.4 'H), 11.33 (2H, s, CO.sub.2.sub.--H × 2)  29 DMSO-d.sub.6      ##STR141##      ##STR142##        C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.26 (1H, d, J = 9.0,     C.sub.3 'H), 7.73 (1H, d, J = 2.5, C.sub.6 'H), 7.80-8.10 (1H,   m,     C.sub.4H), 8.17 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 9.65 (2H, br s,     CO.sub.2.sub.--H × 2)      30 DMSO-d.sub.6     ##STR143##      ##STR144##        C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.60-8.20 (1H, m,     C.sub.4H), 7.72 (1H, d, J = 2.5, C.sub.6 'H), 8.15 (1H, dd,   J = 9.0,     2.5, C.sub.4 'H), 9.73-10.52 (2H, br, CO.sub.2.sub.--H × 2)  31     DMSO-d.sub.6      ##STR145##      ##STR146##        C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d,     J = 2.5, C.sub.6 'H), 7.62-8.17 (1H, m, C.sub.4H), 8.16 (1H,   dd, J =     9.0, 2.5, C.sub.4 'H), 9.32-10.08 (2H, br, CO.sub.2.sub.--H × 2)     32 DMSO-d.sub.6      ##STR147##      ##STR148##        C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.72 (1H, d, J = 2.5,     C.sub.6 'H), 7.57-8.20 (1H, m, C.sub.4H), 8.18 (1H, dd,   J = 9.0, 2.5,     C.sub.4 'H), 9.43-10.13 (2H, br, CO.sub.2.sub.--H × 2)  33     CDCl.sub.3DMSO-d.sub.6      ##STR149##      ##STR150##        7.48-7.92 (2H, m, C.sub.4H and C.sub.3 'H), 7.78 (1H, d, J = 3.0,     C.sub.6 'H), 8.12 (1H, dd, J = 9.0, 3.0, C.sub.4      'H),     ##STR151##      34 DMSO-d.sub.6     ##STR152##      ##STR153##        6.85-7.33 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.38     (1H, d, J = 2.5, C.sub.4 'H), 7.67-8.10 (1H, m, C.sub.4H),   7.78 (1H,     d, J = 2.5, C.sub. 6 'H), 11.05 (2H, br s, CO.sub.2.sub.--H × 2)     35 DMSO-d.sub.6      ##STR154##      ##STR155##        7.70-8.10 (1H, m, C.sub.4H), 11.44 (2H, s, CO.sub.2.sub.--H ×     2)      36 CDCl.sub.3     ##STR156##      ##STR157##        C.sub.4H)      37 DMSO-d.sub.6     ##STR158##      ##STR159##        7.70-8.10 (1H, m, C.sub.4H), 10.00-11.37 (3H, br, CO.sub.2.sub.--H     × 2 and O.sub.--H)      38 DMSO-d.sub.6     ##STR160##      ##STR161##        and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.47-11.07 (1H, br, .sub.--HCl     )      39 DMSO-d.sub.6     ##STR162##      ##STR163##        8.10 (1H, m, C.sub.4H), 7.78 (1H, d, J = 9.0, C.sub.5      ' H), 10.71-11.32 (1H, br, .sub.--HCl)  40 CDCl.sub.3DMSO-d.sub.6      ##STR164##      ##STR165##        8.10 (1H, m, C.sub.4H), 8.23 (1H, d, J = 9.0, C.sub.3      'H), 11.30-12.00 (1H, br, .sub.--HCl)      41 DMSO-d.sub.6     ##STR166##        J = 5.0, OC.sub.--H.sub.2), 6.90-7.40 (4H, m, C.sub.2H, C.sub.5H,     C.sub.6H and C.sub.7H), 6.95 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5     'H),   7.23 (2H, d, J = 9.0, C.sub.2 'H and C.sub.6 'H), 7.80-8.10 (1H,     m, C.sub.4H), 10.90-11.70 (1H, br, .sub.--HCl)      42 DMSO-d.sub.6     ##STR167##      ##STR168##        6.80 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.12 (2H, d, J =     9.0, C.sub.2 'H and C.sub.6      'H), 7.60-8.00 (1H, m, C.sub.4H),   11.00-11.60 (1H, br, .sub.--HCl)     43 DMSO-d.sub.6      ##STR169##      ##STR170##        6.82 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5 'H), 7.29 (2H, d, J =     8.5, C.sub.2 'H and C.sub.6      'H), 7.70-8.10 (1H, m, C.sub.4H),   10.80-11.50 (1H, br, .sub.--HCl)     44 DMSO-d.sub.6      ##STR171##      ##STR172##        6.81 (2H, d, J = 9.0, C.sub.3 'H and C.sub.5 'H), 7.15 (2H, d, J =     9.0, C.sub.2 'H and C.sub.6      'H), 7.70-8.00 (1H, m, C.sub.4H),   10.70-11.30 (1H, br, .sub.--HCl)     45 DMSO-d.sub.6      ##STR173##      ##STR174##        7.30 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and C.sub.7H), 7.21 (2H, d,     J = 8.5, C.sub.2 'H and C.sub.6 'H), 7.70-8.10 (1H, m,   C.sub.4H),     10.50-11.20 (1H, br, .sub.--HCl)      46 DMSO-d.sub.6     ##STR175##        (6H, m, C.sub.--H.sub.2 N(C.sub.--H.sub.2 CH.sub.3).sub.2), 4.03 (2H,     t, J = 6.0, OC.sub.--H.sub.2), 6.80-7.40 (4H, m, C.sub.2H, C.sub.5H,     C.sub.6H and C.sub.7H),   6.83 (2H, d, J = 8.5, C.sub.3 'H and C.sub.5     'H), 7.16 (2H, d, J = 8.5, C.sub.2 'H and C.sub.6 'H), 7.70-8.00 (1H, m,     C.sub.4H),   10.70-11.30 (1H, br, .sub.--HCl)      47 CDCl.sub.3     ##STR176##      ##STR177##        C.sub.2H and ArH), 7.57-8.10 (1H, m, C.sub.4 H), 8.83-9.30 (1H, br,     O.sub.--H)      48 DMSO-d.sub.6     ##STR178##      ##STR179##        7.70-8.10 (1H, m, C.sub.4H), 10.77-11.50 (1H, br, .sub.--HCl)  49     DMSO-d.sub.6      ##STR180##      ##STR181##        7.70-8.10 (1H, m, C.sub.4H), 10.53-11.37 (1H, br, .sub.--HCl)  50     DMSO-d.sub.6      ##STR182##      ##STR183##        ArH), 7.70-8.13 (1H, m, C.sub.4H), 10.67-11.33 (1H, br, .sub.--HCl)

      X NMR No.  δ (ppm) J =      HZ                                             51 DMSO-d.sub.6      ##STR184##      ##STR185##        C.sub.2H and ArH), 7.73-8.10 (1H, m, C.sub.4H), 10.50-11.07 (1H, br,     .sub.--HCl)      52 DMSO-d.sub.6     ##STR186##      ##STR187##        (1H, m, C.sub.4H), 7.33 (1H, dd, J = 9.0, 2.5, C.sub.6 'H), 7.78 (1H,     d, J = 2.5, C.sub.2 'H), 11.17-11.85 (1H, br, .sub.--HCl)      53 DMSO-d.sub.6      ##STR188##      ##STR189##        6.98 (1H, s, C.sub.2H), 6.93-7.33 (3H, m, C.sub.5H, C.sub.6H and     C.sub.7H), 7.80-8.00 (1H, m, C.sub.4H), 10.90-11.40   (1H, br, .sub.--HCl     )      54 DMSO-d.sub.6     ##STR190##      ##STR191##        and C.sub.6 'H), 7.01 (1H, s, C.sub.2H), 7.00-7.40 (3H, m, C.sub.5H,     C.sub.6H and C.sub.7H), 7.77-8.10 (1H, m, C.sub.4H),   10.68-11.20 (1H,     br, .sub.--HCl)      55 DMSO-d.sub.6     ##STR192##      ##STR193##        C.sub.6 'H), 7.00-7.50 (4H, m, C.sub.2H, C.sub.5H, C.sub.6H and     C.sub.7H), 7.80-8.10 (1H, m, C.sub.4H), 10.70-11.20 (1H, br,   .sub.--HCl     )      56 DMSO-d.sub.6     ##STR194##      ##STR195##        C.sub.4H), 11.20-12.50 (2H, br, .sub.--HCl × 2)      57 DMSO-d.sub.6      ##STR196##      ##STR197##        11.77-13.03 (4H, br, CO.sub.2.sub.--H × 4)  58 DMSO-d.sub.6      ##STR198##        3.73 (3H, s, OC.sub.--H.sub.3 (A)), 3.77 (3H, s, OC.sub.--H.sub.3     (A)), 4.17 (2H, br t, J = 5.0, OC.sub.--H.sub.2), 6.13 (4H, s,      ##STR199##        CO.sub.2.sub.--H × 4)      59 DMSO-d.sub.6     ##STR200##      ##STR201##      ##STR202##      60 DMSO-d.sub.6     ##STR203##      ##STR204##        and ArH), 7.67-8.20 (1H, m, C.sub.4H), 10.87 (2H, br s, CO.sub.2.sub.-     -H ×  2)      61 DMSO-d.sub.6     ##STR205##        3.78 (3H, s, OC.sub.--H.sub.3 (A)), 3.82 (3H, s, OC.sub.--H.sub.3     (A)), 4.20 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.62-7.70 (13H, m,      ##STR206##      62 DMSO-d.sub.6     ##STR207##        3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3     (A)), 3.73 (3H, s, OC.sub.--H.sub.3 (A)), 4.10 (2H, br t, J = 5.0,      ##STR208##        7.68-8.20 (1H, m, C.sub.4H), 11.37-12.83 (4H, br, CO.sub.2.sub.--H     × 4)      63 DMSO-d.sub.6     ##STR209##        3.55 (3H, s, OC.sub.--H.sub.3 (P)), 3.67 (3H, s, OC.sub.--H.sub.3     (A)), 3.70 (3H, s, OC.sub.--H.sub.3      (A)), 3.87-4.32 (2H, m, OC.sub.--H.sub.2),      ##STR210##        (1H, m, C.sub.4H), 10.83 (4H, br s, CO.sub.2.sub.--H × 4)  64     DMSO-d.sub.6      ##STR211##        3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3     (A)), 3.74 (3H, s, OC.sub.--H.sub.3      (A)), 3.80-4.30 (2H, m, OC.sub.--H.sub.2),      ##STR212##        (1H, m, C.sub.4H), 10.90-12.20 (4H, br, CO.sub.2.sub.--H × 4)     65 DMSO-d.sub.6      ##STR213##        3.57 (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (3H, s, OC.sub.--H.sub.3     (A)), 3.73 (3H, s, OC.sub.--H.sub.3      (A)), 3.87-4.33 (2H, m, OC.sub.--H.sub.2),      ##STR214##        m, C.sub.4H), 11.17-12.67 (4H, br, CO.sub.2.sub.--H × 4)  66     DMSO-d.sub.6      ##STR215##        3.53 (3H, s, OC.sub.--H.sub.3 (P)), 3.65 (2H, t, J =      5.5, C.sub.--H.sub.2 OH), 3.87-4.23 (2H, m, OC.sub.--H.sub.2), 6.12     (4H, s,      ##STR216##        9.20-11.20 (5H, br, CO.sub.2.sub.--H × 4 and O.sub.--H)  67     DMSO-d.sub.6      ##STR217##        3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.64 (3H, s, OC.sub.--H.sub.3     (A)), 3.78 (6H, s, OC.sub.--H.sub.3 × 2(A)), 3.84-4.30 (2H, m,      ##STR218##        7.80-8.10 (1H, m, C.sub.4H), 11.00-13.50 (2H, br, .sub.--HCl ×     2)      68 DMSO-d.sub.6     ##STR219##        3.56 (3H, s, OC.sub.--H.sub.3 (P)), 3.74 (3H, s, OC.sub.--H.sub.3     (A)), 3.77 (3H, s,  OC.sub.--H.sub.3 (A)), 3.79 (3H, s, OC.sub.--H.sub.3     (A)),      ##STR220##      ##STR221##      ##STR222##      69 DMSO-d.sub.6     ##STR223##      ##STR224##      ##STR225##        br s, CO.sub.2.sub.--H ×  4)      70 DMSO-d.sub.6     ##STR226##        3.59 (3H, s, OC.sub.--H.sub.3 (P)), 3.74 (3H, s, OC.sub.--H.sub.3     (A)), 3.82 (6H, s, OC.sub.--H.sub.3 × 2(A)), 3.93-4.23 (2H, m,      ##STR227##        7.37 (6H, m, C.sub.2H and ArH), 7.67-8.13 (1H, m, C.sub.4H), 9.50-11.5     0 (4H, br, CO.sub.2.sub.--H × 4)      71 DMSO-d.sub.6     ##STR228##        (3H, s, OC.sub.--H.sub.3 (P)), 3.70 (6H, s, OC.sub.--H.sub.3 ×     2(A)), 4.03 (2H, t, J = 5.0, OC.sub.--H.sub.2), 6.45 (1H, d, J = 2.0,      ##STR229##        br s, CO.sub.2.sub.--H × 2)      72 DMSO-d.sub.6     ##STR230##      ##STR231##      ##STR232##        7.70-8.10 (1H, m, C.sub.4H), 9.83-12.00 (2H, br, CO.sub.2.sub.--H     × 2)      73 DMSO-d.sub.6     ##STR233##      ##STR234##        m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.75 (1H,     d, J = 2.5, C.sub.6 'H), 7.70-8.37 (1H, m, C.sub.4H), 8.23 (1H,   dd, J     = 9.0, 2.5, C.sub.4 'H), 11.30-12.50 (4H, br, CO.sub.2 .sub.--H ×     4)      74 DMSO-d.sub.6     ##STR235##      ##STR236##      ##STR237##        7.72 (1H, d, J = 2.5, C.sub.6 'H), 7.77-8.10 (1H, m, C.sub.4H), 8.17     (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 11.00-12.27   (4H, br, CO.sub.2     .sub.--H × 4)      75 DMSO-d.sub.6     ##STR238##      ##STR239##        6.75-7.48 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3  H     '), 7.63 (1H, d, J = 2.5, C.sub.6 'H), 7.65-8.25 (2H, m,   C.sub.4H and     C.sub.4 'H), 10.38 (2H, br s, CO.sub.2 .sub.--H × 2)      76 DMSO-d.sub.6      ##STR240##      ##STR241##        8.19 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 10.50-11.92 (4H, br,     CO.sub.2 .sub.--H × 4)      77 DMSO-d.sub.6     ##STR242##      ##STR243##        6.80-7.42 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3  H     '), 7.28 (5H, s, C.sub.6 .sub.--H.sub.5), 7.62-8.32 (1H, m, C.sub.4H),     7.69 (1H, d, J = 2.5, C.sub.6 'H), 8.14 (1H, dd, J = 9.0, 2.5, C.sub.4     'H), 9.00-11.75 (5H, br, CO.sub.2 .sub.--H × 4 and O.sub.--H)  78     DMSO-d.sub.6      ##STR244##      ##STR245##        m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3 'H), 7.67-8.51     (3H, m, C.sub.4H, C.sub.4 ' H and C.sub.6 'H), 7.88 (2H, d, J = 8.8,      ##STR246##      79 DMSO-d.sub.6     ##STR247##      ##STR248##      ##STR249##        C.sub.4 'H), 11.64-12.51 (1H, br, .sub.--HCl)      80 CDCl.sub.3     ##STR250##        3.81 (3H, s, OC.sub.--H.sub.3 (A) ), 3.84 (3H, s, OC.sub.--H.sub.3     (A) ), 3.90 (3H, s, OC.sub.--H.sub.3      (P) ), 4.20-4.65 (2H, m, OC.sub.--H.sub.2),      ##STR251##        and .sub.--HCl × 2), 7.50 (1H, d, J = 2.5, C.sub.4 'H), 7.67     (1H, d, J = 2.5, C.sub.6 'H)      81 DMSO-d.sub.6     ##STR252##        3.70 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.73 (3H, s,     OC.sub.--H.sub.3 (A) ), 3.73-4.07 (2H, m, OC.sub.--H.sub.2), 6.13 (4H,     s,      ##STR253##        CO.sub.2 .sub.--H × 4)      82 DMSO-d.sub.6     ##STR254##      ##STR255##        6.63-7.32 (11H, m, C.sub.2H and ArH), 7.69-8.10 (1H, m, C.sub.4H),     11.42 (4H, s. CO.sub.2 .sub.--H × 4)      83 DMSO-d.sub.6     ##STR256##        3.67 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.70 (3H, s,     OC.sub.--H.sub.3 (A) ), 3.93 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.10     (4H, s,      ##STR257##      84 DMSO-d.sub.6     ##STR258##        3.70 (6H, s, OC.sub.--H.sub.3 × 2 (P, A) ), 3.73 (3H, s,     OC.sub.--H.sub.3 (A) ), 3.97 (2H, t, J = 6.0, OC.sub.--H.sub.2), 6.12     (4H, s,      ##STR259##      85 DMSO-d.sub.6     ##STR260##        3.63 (6H, s, OC.sub.--H.sub.3 ×      2 (P) ), 3.70 (3H, s, OC.sub.--H.sub.3 (A) ), 3.70-4.10 (2H, m,     OC.sub.--H.sub.2), 3.73 (3H, s, OC.sub.--H.sub.3      (A) ),     ##STR261##        (1H, m C.sub.4H), 10.50-12.00 (4H, br, CO.sub.2 .sub.--H × 4)     86 CDCl.sub.3      ##STR262##      ##STR263##        7.50-8.50 (1H, m, C.sub.4H), 8.00-10.00 (2H, br, N.sub.--Hand     .sub.--HCl)      87a DMSO-d.sub.6     ##STR264##      ##STR265##        7.50 (8H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H), 9.90-11.0     0 (1H, br, .sub.--HCl)      87b DMSO-d.sub.6     ##STR266##      ##STR267##        ArH), 7.70-8.27 (1H, m, C.sub.4H), 9.70-10.80 (1H, br, .sub.--HCl)     88 CDCl.sub.3 1.43 (6H, t, J = 7.0, N(CH.sub.2 C.sub.--H.sub.3).sub.2),     2.32 (3H, s, COC.sub.--H.sub.3), 3.10-3.70 (6H, m, C.sub.--H.sub.2     N(C.sub.--H.sub.2 CH.sub.3).sub.2), 3.9-4.7   2H, m, OC.sub.--H.sub.2     CH), 4.50-5.00 (1H, br, C.sub.--H(OH)), 5.50-6.10 (1H, br, O.sub.--H),     6.60-7.40 (8H, m, C.sub.2H   and ArH), 7.50-8.30 (1H, m, C.sub.4H),     10.50-11.40 (1H, br, .sub.--HCl)      89 DMSO-d.sub.6     ##STR268##      ##STR269##        (1H, m, C.sub.4H), 10.90-11.50 (1H, br, .sub.--HCl)  90 DMSO-d.sub.6      ##STR270##      ##STR271##        C.sub.4H)      91 DMSO-d.sub.6     ##STR272##      ##STR273##        (1H, m, C.sub.4H), 10.37 (2H, br s, CO.sub.2 .sub.--H × 2)  92     DMSO-d.sub.6      ##STR274##      ##STR275##        6.80-7.50 (11H, m, C.sub.2H and ArH), 7.80-8.20 (1H, m, C.sub.4H),     9.20-9.83 (2H, br, CO.sub.2 .sub.--H × 2)      93 CDCl.sub.3     ##STR276##        3.58 (3H, s, OC.sub.--H.sub.3      (P) ), 3.85-4.50 (2H, m, OC.sub.--H.sub.2 ), 6.43 (1H, d, J = 2.0,     C.sub.6 'H), 6.67-8.12 (12H, m,   C.sub.2H and ArH), 8.13 (2H, br s,     CO.sub.2 .sub.--H × 2)      94 DMSO-d.sub.6     ##STR277##        4.06 (1H, m, C.sub.--HOH), 4.10-4.69 (2H, m, OC.sub.--H.sub.2),     6.86-7.60 (5H, m, C.sub.2H, C.sub.5H, C.sub.6H, C.sub.7H and C.sub.3     'H),   7.71 (1H, d, J = 2.5, C.sub.6 'H), 7.83-8.49 (1H, m, C.sub.4H),     8.13 (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 8.18 (3H, s,   CO.sub.2     .sub.--H × 2 and O.sub.--H)      95 DMSO-d.sub.6     ##STR278##        4.61 (2H, m, OC.sub.--H.sub.2), 6.89-7.55 (10H, m, C.sub.2H and ArH),     7.70 (1H, d, J = 2.5, C.sub.6 'H), 7.81-8.31 (1H,   m, C.sub.4H), 8.28     (1H, dd, J = 9.0, 2.5, C.sub.4 'H), 9.48 (2H, br s, CO.sub.2 .sub.--H     × 2)  96 CDCl.sub.3 1.88-2.85 (4H, m, OCH.sub.2 C.sub.--H.sub.2     C.sub.--H.sub.2 CO.sub.2 H), 2.20 (3H, s, COC.sub.--H.sub.3), 4.10 (2H,     t, J = 5.5, OC.sub.--H.sub.2), 6.60-7.50   (8H, m, C.sub.2H and ArH),     7.70-8.50 (1H, m, C.sub.4H), 10.88 (1H, br s, CO.sub.2 .sub.--H)  97     CDCl.sub.3 1.27 (3H, t, J = 7.0, CO.sub.2 CH.sub.2 C.sub.--H.sub.3),     1.88-2.80 (4H, m, OCH.sub.2 C.sub.--H.sub.2 C.sub.--H.sub.2 CO.sub.2),     2.20 (3H, s, COC.sub.--H.sub.3), 4.12   (2H, t, J =                      )      6.0, OC.sub.--H.sub.2, 4.18 (2H, q, J = 7.0, CO.sub.2 C.sub.--H.sub.2     CH.sub.3), 6.60-7.40 (8H, m, C.sub.2H and ArH), 7.80-8.50   (1H, m,     C.sub.4H)      98 CDCl.sub.3     ##STR279##        (2H, q, J = 7.0, NHC.sub.--H.sub.2      CH.sub.2), 3.77 (3H, s, OC.sub.--H.sub.3      (A) ), 3.82 (3H, s, OC.sub.--H.sub.3 (A) ), 4.08 (2H, t, J = 5.5,     OC.sub.--H.sub.2), 5.70-6.20 (1H, br, N.sub.--H), 6.50-7.50 (11H, m,     C.sub.2H and ArH), 7.60-8.50 (1H, m, C.sub.4H)      99 DMSO-d.sub.6     ##STR280##      ##STR281##        ArH), 7.80-8.20 (1H, m, C.sub.4H), 10.70 (2H, br s, CO.sub.2 .sub.--H     ×  2)  100       CDCl.sub.3     ##STR282##        t, J = 5.5, OC.sub.--H.sub.2), 6.60-7.40 (8H, m, C.sub.2H and ArH),     7.70-8.50 (1H, m, C.sub.4H)

Pharmacological Activities

Calcium antagonists have not only potentially beneficial effects in thetreatment of many diseases but also serve as valuable research tools toelucidate excitation-contraction coupling in various muscle types (A.Fleckenstein, Ann. Rev. Pharmacol., 17, 149-166, 1977). Therefore, weexamined the calcium-antagonistic activity of the compounds of thisinvention.

Pharmacological test I

The action potentials on the smooth muscles of uterus, teania coli andportal vein are dependent on calcium ion, and therefor these smoothmuscle preparations are useful for screening of calcium antagonists. Wemeasured the calcium-antagonistic activity of the compounds by themethod using guinea-pig teania coli preparation.

Isolated guinea-pig teania coil was suspended in a 20 ml organ bath withKrebs solution at 32° C. and bubbled with 5% carbon dioxide in oxygen.After equilibration, the muscle was washed with Ca⁺⁺ -free Krebssolution, and when the muscle had relaxed to basal level, it wassuspended in Ca⁺⁺ -free-high-K Krebs solution.

The muscle was exposed to test compounds for 5 minutes before additionof CaCl₂, and the contraction evoked by CaCl₂ (3×10⁻⁴ M) was recordedisotonically. The calcium-antagonistic activity was represented by theconcentration of test compound which elicited 50% inhibition of Ca⁺⁺-evoked contraction (IC₅₀).

As shown in Table XI, the compounds of this invention hadcalcium-antagonistic activity.

Blood platelet plays an important role only in hemostasis but also inthrombosis. Platelet hyperaggregability leads to an inclease in thenumber of circulating platelet aggregates, which may contribute towardthe development of cardiac arrythmias, cardiac arrest or myocardialinfarction. These cardiovascular diseases can be prevented by inhibitionof platelet aggregation. Therefor, we screened the influence of testcompounds on platelet aggragation in vitro, and found that they haveanti-aggregatory activity.

Pharmacological test II

Blood was obtained from an anesthetized rabbit using 0.1 volumes of 3.8%sodium citrate as anticoagulant. Platelet rich plasma(PRP) was isolatedby centrifugation at 650 rpm for 10 minutes at room temperature. Afterpreincubation of PRP (0.25 ml) with various concentrations of testcompounds (14 μl) for 1 minute at 37° C., collagen (3 μg/ml:finalconcentration) or ADP (3 μM:final concentration) was added to induceaggregation and the aggregation profiles were monitored with RIKADENKIsix-channel aggregometer. The control experiment contained salineinstead of test compound.

The anti-aggregatory activity was represented by the concentration oftest compound which elicited 50% inhibition of control response.

As shown in the Table XII, the compounds of this invention hadanti-aggregatory activity.

                  TABLE XI                                                        ______________________________________                                        Calcium-antagonistic activity                                                 Compound No.    IC.sub.50 [M]                                                 ______________________________________                                        23              6.6 × 10.sup.-7                                         33              5.2 × 10.sup.-7                                         63              6.4 × 10.sup.-7                                         67              4.7 × 10.sup.-7                                         ______________________________________                                    

                  TABLE XII                                                       ______________________________________                                        Anti-aggregatory activity                                                     Compound No.    IC.sub.50 [M]                                                 ______________________________________                                         8              4.6 × 10.sup.-6                                         21              1.3 × 10.sup.-6                                         22              1.1 × 10.sup.-6                                         29              3.2 × 10.sup.-6                                         54              3.1 × 10.sup.-6                                         55              2.0 × 10.sup.-6                                         95              2.7 × 10.sup.-6                                         ______________________________________                                    

Toxicity test

Acute toxicity of the compounds of this invention is shown in TableXIII.

(animal)

Male ddy-SLC strain rats (4 weeks of age, weighing 19-21 g) were placedin a breeding room of constant temperature and huminity (23±1° C.,55±5%) and fed freely pellet diet and water ad. libitum for a week. Ratsshowing normal growth were selected for the test.

(method of administration)

Test compounds are suspended in 0.5% tragacanth suspention andadministered orally in a dose of 0.5 ml/20 g body weight.

                  TABLE XIII                                                      ______________________________________                                        Compound No.   LD.sub.50 (mg/kg)                                              ______________________________________                                        29             >2,000                                                         63             ≧3,000                                                  67             >1,000                                                         ______________________________________                                    

The compounds can be administered either orally or parenterally. Thedosage forms are tablet, capsule, granule, powder, suppository,injection, etc. The dose is adjusted depending on symptom, dosage form,etc., but usual daily dosage is 1 to 5,000 mg, preferably 10 to 1,000mg, in one or a few divided doses.

Examples of formulation are shown below.

    ______________________________________                                        Example of formulation                                                        ______________________________________                                        (a) tablet                                                                    compound 8               30     mg                                            lactose                  150    mg                                            crystalline cellulose    50     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    240    mg                                            ______________________________________                                        compound 21              50     mg                                            lactose                  120    mg                                            crystalline cellulose    60     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    240    mg                                            ______________________________________                                        compound 22              60     mg                                            lactose                  120    mg                                            crystalline cellulose    60     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    250    mg                                            ______________________________________                                        compound 23              40     mg                                            lactose                  150    mg                                            crystalline cellulose    50     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    250    mg                                            ______________________________________                                        compound 33              70     mg                                            lactose                  110    mg                                            crystalline cellulose    60     mg                                            calcium carboxymethylcellulose                                                                         7      mg                                            magnesium stearate       3      mg                                            total                    250    mg                                            ______________________________________                                    

The tablets may be treated with the common film-coating and further withsugar-coating.

    ______________________________________                                        (b) granule                                                                   compound 63            30     mg                                              polyvinylpyrrolidone   25     mg                                              lactose                385    mg                                              hydroxypropylcellulose 50     mg                                              talc                   10     mg                                              total                  500    mg                                              ______________________________________                                        compound 29            50     mg                                              polyvinylpyrrolidone   25     mg                                              lactose                365    mg                                              hydroxypropylcellulose 50     mg                                              talc                   10     mg                                              total                  500    mg                                              ______________________________________                                        (c) powder                                                                    compound 54            30     mg                                              lactose                500    mg                                              starch                 440    mg                                              colloidal silica       30     mg                                              total                  1000   mg                                              ______________________________________                                        compound 67            50     mg                                              lactose                480    mg                                              starch                 440    mg                                              colloidal silica       30     mg                                              total                  1000   mg                                              ______________________________________                                        (d) capsule                                                                   compound 55            30     mg                                              lactose                102    mg                                              crystalline cellulose  56     mg                                              colloidal silica       2      mg                                              total                  190    mg                                              ______________________________________                                        compound 95            50     mg                                              glycerol               329.8  mg                                              butyl p-hydroxybenzoate                                                                              0.02   mg                                              total                  380    mg                                              ______________________________________                                    

UTILITY IN AN INDUSTRIAL FIELD

This invention offers novel compounds which are useful for therapeuticagent.

What we claim is:
 1. A compound of the formula (I) and salts thereof,##STR283## wherein R¹ is lower alkanoyl;R² is one to three groupsselected from hydrogen, lower n-alkyl, lower n-alkoxy, hydroxy, chloro,bromo, nitro, halogeno-lower alkyl and sulfamoyl; R³ is --COR⁸ ; R⁸ ishydroxy, lower alkoxy, ##STR284## R⁴ and R⁵, which may be same ordifferent, each is hydrogen, lower alkyl, cyclohexyl or substitutedlower alkyl, said substituted lower alkyl has at least one substituentselected from the group consisting of hydroxy, phenyl, pyridyl,piperidyl and phenylcarbonyl, and said phenyl nucleus may be substitutedby one to three groups selected from lower n-alkyl, hydroxy, chloro,bromo, lower n-alkoxy, nitro, cyano, acetamino and lower n-alkylamino;R⁶ is hydrogen, alkyl having 1 to 8 carbon atoms, alkanoyl having 2 to 8carbon atoms, alkenoyl having 2 to 8 carbon atoms or furylcarbonyl, eachof which alkyl, alkanoyl and alkenoyl may be substituted by one to threegroups selected from hydroxy, phenyl and phenylcarbonyloxy, and saidphenyl nucleus may be substituted by one to three groups selected fromlower n-alkyl, hydroxy, chloro, bromo, lower n-alkoxy, nitro, cyano,acetamino and lower n-alkylamino; Z is straight or branched alkylenehaving 1 to 6 carbon atoms; m is 0 or 1;wherein the terms lower alkyl,lower alkoxy and lower alkanoyl refer to groups having 1 to 6 carbonatoms.
 2. A compound as in claim 1 wherein m is
 0. 3. A compound as inclaim 1 wherein m is 1 , n is 1 and Z is --CH₂ --.
 4. A compound as inclaim 1 wherein R¹ is acetyl.
 5. A compound as in claim 1 wherein R² ishydrogen.
 6. A compound as in claim 2 wherein R² is methoxy or nitro. 7.A compound as in claim 2 wherein R⁸ is --N(R⁴) (R⁵), R⁴ is hydrogen andR⁵ is 2-(3,4-dimethoxyphenyl)ethyl.
 8. A compound as in claim 2 whereinR⁸ is ##STR285## and R⁶ is methyl. 9.3-Acetyl-2-[2-[3-(4-methyl-1-piperazinylcarbonyl)propoxy]phenyl]benzothiazolineof the formula of claim
 1. 10. A pharmaceutical composition comprising(i) a compound as in claim 1 in an amount sufficient for treatment forcardiovascular diseases and at least one pharmaceutically acceptableexcipient.
 11. A method of treatment for cardiovascular diseases whichcomprises administering a composition comprising a compound as in claim1 and at least one pharmaceutically acceptable excipient.